Why would lowering the temperature of water change the intermolecular forces so much that proteins once soluble in water, become insoluble? I know freezing can create a crystal lattice, but I don't see how temperature would connect to the inter-molecular forces of water? If it even does?

EDIT: So why would a temperature decrease change how a protein interacts with a POLAR solvent


2 Answers 2


This answer is about cold denaturation of proteins rather than the effect of freezing.

The folded structure of a protein is thermodynamically stable as a result of a small favourable difference between the free energies of the folded and unfolded states. For a small single-domain protein this difference is usually only equivalent to the strength of a small number of hydrogen bonds - folded states are not very stable.

Electrostatic interactions, hydrogen bonds, and van der Waals interactions within the protein, interactions within the solvent, and interactions between the protein and the solvent all have to be considered, together with any entropic effects.

One factor that plays a part is the effect that an exposed non-polar group from the protein can have upon the solvent. Because the water molecules next to such a non-polar group cannot form hydrogen bonds with it they become more ordered or ice-like as they can only hydrogen bond with each other. This is the basis of the hydrophobic effect - as a protein folds and sequesters its non-polar groups in the protein interior then the unfavourable entropy change in the protein (i.e. it has become more ordered) is offset by the increased disorder in the water.

As the temperature falls the water becomes more structured anyway, so an increase in entropy of the water is no longer available to offset the decreased entropy of the folded polypeptide. The thermodynamic balance sheet is altered and the unfolded state is favoured.


If proteins change from being water soluble to water insoluble it means that their three-dimensional structure changed, because this determines how the protein interacts with the water. Most proteins have hydrophilic residues on the outside in their normal structure configuration, which makes the soluble. If this changes and some of the hydrophobic residues come to the protein surface the protein may not be soluble anymore.

The process of the structure changing (sometimes also called 'denaturing') can be caused by a lot of different factors - basically everything that is different from the inside of a cell (for humans: ~37°, salt concentrations, ...). If water freezes then the ice-crystal lattice can force the proteins out of their normal conformation/structure, after thawing the ice they may not get their structure back on their own (this depends on the protein).

To give an answer to your edit: the temperature does not affect the solubility directly, the effect is indirect through a change in structure

  • $\begingroup$ I am asking what physical and or chemical properties of the water and or the protein. make a protein go from being soluble to insoluble in a POLAR solvent such as water. Regardless of the temperature of the solution, the solvent remains polar. So why would a temperature decrease change how a protein interacts with a POLAR solvent $\endgroup$ Commented Jun 25, 2017 at 6:05
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    $\begingroup$ @Confusedbyeverything I already explained that: the change in temperature/crystal formation changes the structure of the protein, this in turn changes which residues of the proteins interact with the water/solvent, which changes its solubility $\endgroup$
    – Nicolai
    Commented Jun 25, 2017 at 6:25
  • $\begingroup$ Here is my confusion: how do the changes in the temperature/crystal formation change the structure of the protein and why would this favor the formation of an insoluble form ? I understand how PH, salts, inter-molecular forces, can effect protein folding. I can even understand how temperature can denature a protein by offering it more energy to undergo different chemical reactions, but what is the underlying concept that explains the change from soluble to insoluble when we decrease the temperature? PS I am not a chemistry major so thanks in advance $\endgroup$ Commented Jun 25, 2017 at 9:28

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